**5. Conclusion**

Atorvastatin has been shown to reduce small dense LDL subfractions, remnant-like particles cholesterol and oxLDL, and improve endothelial function, after just few weeks of therapy [55,56]. Such time-related effect has not been fully elucidated, but may possibly account for our finding that in the first six months there was an accelerated decline of oxLDL levels

Additional pleiotropic effects of statins have been reported in the literature and might account for the observed beneficial effects in the current study. Lysophosphatidylcholine is elevated during LDL oxidation and is responsible for some of the biological effects of oxLDL. Atorvas‐ tatin alters the ability of oxLDL to impair the endothelium relaxation, by modulating the hydrolysis of phosphatidylcholine to lysophosphatidylcholine when LDL is being oxidized [57]. Statins remove predominately "aged LDL" from plasma, which is more prone to oxidation [53], through stimulation of hepatic LDL receptor activity and inhibition of very-low density lipoprotein (VLDL) and LDL production by the liver cells [53]. Statins also reduce oxygen species generation [54]. Atorvastatin promotes adipocyte uptake of oxLDL in rabbits by increasing the expression of CD36 and peroxisome proliferators-activated receptor γ (PPARγ) in adipocytes [58]. The increased expression of such receptors by adipocytes results to internalization of oxLDL and clearance from plasma, converting adipocytes to an oxLDLbuffering pool [58]. Reduction of oxLDL in patients with CHD with atorvastatin 10mg parallel with an increase of adiponectin, which has anti-atherogenic [55], anti-inflammatory and antidiabetic [55] properties through reduction of insulin resistance [55]. The CARDS study reported a significant degree of preventive activity of atorvastatin against myocardial infarc‐ tion in eucholesterolemic diabetic patients, conceivably attributed to such improvement of insulin sensitivity [55]. Statins also diminish the expression of CD40 and CD40 ligand in vascular cells, smooth muscle cells and macrophages, which are promoted by oxLDL and are considered proatherogenic [59]. Other anti-inflammatory pathways include reduction of Creactive protein [60], chemokines, major histocompatibility complex II molecules, matrixdegrading enzymes, and procoagulant tissue factor [59]. Atorvastatin reverses the oxLDLmediated inhibition of vascular endothelial growth factor-induced endothelial progenitor cell differentiation via the phosphatidylinositol 3 kinase/Akt pathway [61], which restores the oxLDL-related inhibition of mature endothelial cells migration [61]. This could improve neovascularization and collateral vessel formation in response to tissue ischemia. Atorvastatin also suppresses platelet activity [62] by reducing the expression of CD36 and LOX-1, which are present in platelets [43,62], thus inhibiting the oxLDL-mediated platelet hyperactivity [62]. Statins reduce the oxLDL-derived expression of adhesion molecules (E- and P-selectins, vascular cell adhesion molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]) in human coronary artery endothelial cells [15], through up-regulation of eNOS expression [15], which regulates the expression of adhesion molecules in endothelial cells [15]. Statins also diminish the oxLDL-mediated activation of nuclear factor-κΒ (NF-κB) [15], which regulates the transcription of adhesion molecule genes [33]. In diabetic patients with dyslipidemia atorvastatin reduced CVD and markers of inflammation, adhesion and oxidation, such as CRP, soluble ICAM-1, soluble VCAM-1, E-selectin, matrix metalloproteinase 9, secretory phospho‐ lipase A2 (sPLA2), and oxLDL, the latter by 38,4% [60]. Moreover, the change of oxLDL levels correlated with the change of sICAM-1 and E-selectin levels, suggesting that statins could

followed by a milder reduction rate thereafter.

140 Carotid Artery Disease - From Bench to Bedside and Beyond

This prospective, cross-sectional study with such a long observation period provided enough evidence to postulate a favourable effect of low-dose atorvastatin therapy on oxLDL, which was additionally associated with improvement of stenosis in patients with carotid atheroma‐ tosis. We thus, assume that oxidised LDL may represent a far more sensitive risk factor for carotid stenosis, than LDL itself or apoB. Further studying is required to confirm such findings and to establish a clear clinical and pathophsiologic link between oxLDL and carotid stenosis.

[4] Anderson TJ, Meredith IT, Charbonneau F, et al. Endothelium – dependant coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation

Oxidised Low Density Lipoprotein (LDL) Modification with Statin Therapy is Associated with...

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